Cardiac and cerebral thrombosis are common diseases, of which coronary thrombosis and cerebral thrombosis, as the main thrombosis diseases, are taking place increasingly in recent years and greatly affecting people's health. The preventive and therapeutic researches of these diseases are very important. Platelet aggregation is a key step in normal blood agglutination mechanism. Both platelet adhesion and aggregation are the major initial steps in thromogenesis. Therefore, pharmaceuticals for the inhibition of platelet aggregation play a very important role in the treatment of thrombotic diseases, and the invention of anti-thrombosis drugs is always a hot topic in the research of such fields.
Clopiodogrel is a novel high effective and safety anti-thrombosis drug with the structure of (S)-(+)-Clopidogrel bisulfate (XII, wherein: X=2−Cl). Which was first of all disclosed in FR 2215948, FR 2530247 and FR 2612929 by French Sanofi Co., and was invented successfully in 1986. Clinically this drug is used in the treatment of atherosclerosis, acute coronary syndrome (ACS) and thrombosis complication. Clopidogrel was first marketed in United States on March 1998, and later was entered into markets of Europe, Canada, Australia and Singapore etc., and the demands are increased gradually in worldwide.
                Formula (I) is the racemic compound of Clopidogrel and its analogue methyl tetrahydrothieno[3,2-c]pyridine acetate        
As reported, the present methods (U.S. Pat. No. 4,529,596, GB 0420706, GB 0466569, U.S. Pat. No. 5,204,469, EP 465358, EP99802, EP 420706) to obtain Clopiodogrel and compound of formula (XII) is generally performed by using α-halogen phenylacetic acid derivatives as starting raw material to react and derivatize with thiophenylethylamine. In the mentioned methods, compound of formula (IV) and its analog acetonitrile derivatives (WO9851689, WO9851681) could not be hydrolyzed directly to obtain compound of formula (V) or compound of formula (VI). All of them are indirectly hydrolyzed into tetrahydrothienopyridine acetamide derivatives of formula (VII) and further hydrolyzed to obtain compound of formula (I) (WO02059128, CN1487943A).
Recently, Cadila Heath Care LTD of India reported a method for the preparation of compound in formula (IV) (WO02059128, CN 1487943A), in which the compound of formula (IV) could be used to prepare compound of formula (VII) effectively in suitable conditions, and then derivatized to prepare compound of formula (V), compound of formula (VI) and compound of formula (I). In their preparation example, however, did not provide example of alkaline hydrolysis. In fact, we had carried out the preparation according to the method and conditions those they provided, but only could obtain compound of formula (VII), or though we can obtain compound of formula (V) and compound of formula (VI) but with no separation and manufacturing values due to too low yield. In the mean time, the acid hydrolysis method and conditions that patent provided also have no competitive ability due to too low yield (only 38%).
The preparation of the target products and related intermediates can also refer to following references and patents: Journal of Chinese Pharmaceutical Industry 2002, 33 (4) 206, WO9851681, WO9851682, WO9851689, WO9918110, U.S. Pat. No. 4,876,362, U.S. Pat. No. 5,036,156, U.S. Pat. No. 5,132,435, U.S. Pat. No. 5,139,170, U.S. Pat. No. 5,204,469 and U.S. Pat. No. 6,080,875 etc.
Clopidogrel possesses one asymmetric carbon with two chiral isomers, i.e., a (S)-Clopidogrel and a (R)-Clopidogrel. Only (S)-Clopidogrel and its salts possess physiological activities.
(S)-Clopidogrel and the needed chiral intermediates can be obtained from the above mentioned chiral compound synthetic methods or resolution of racemic Clopidogrel and correspondent intermediates (U.S. Pat. No. 6,737,411B2, WO2004074215, U.S. Pat. No. 4,847,265, U.S. Pat. No. 6,215,005B1, U.S. Pat. No. 6,258,961B1).
U.S. Pat. No. 6,737,411B2 reported a process for the synthesize salts of (S)-Clopidogrel by reacting a mixture of (S)- and (R)-Clopidogrel free base with 0.6-0.8 molar of levorotatory camphor sulfonic acid to form camphor sulfonate in a solvent of a C5-C12 hydrocarbon such as benzene, toluene, xylene, chlorobenzene and a solvent mixture of DMF, butanol or acetone etc. to perform resolution by crystallization, and then synthesize the (S)-Clopidogrel and its salts.
WO2004074215 reported a process for preparation of (S)-Clopidogrel and its salts while using more concentrated than 1 molar levorotatory camphor sulfonic acid in large amount of isopropanol to prepare low yielding (<50%) (S)-Clopidogrel camphor sulfonate by resolution with crystallization and then synthesize the (S)-Clopidogrel and its salts.
U.S. Pat. No. 4,847,265 reported a process to obtain target chiral isomers by levorotatory camphor sulfonic acid in solvents such as DMF, ketones and alcohols etc. from resolution of compounds in the form of (S)-Clopidogrel levorotatory camphor sulfonate.
In earlier patents such as U.S. Pat. No. 5,132,435, U.S. Pat. No. 6,215,005, U.S. Pat. No. 6,258,961 and their cited patents and literatures, almost all the chiral resolution strategies were based on the different solubilities between (S)-Clopidogrel camphor sulfonate and (R)-Clopidogrel camphor sulfonate in acetone.
Summarily, the present reported methods or processes for chiral resolution to separate the racemic Clopidogrel are almost all based on the different solubilities between (S)-Clopidogrel camphor sulfonate and (R)-Clopidogrel camphor sulfonate in acetone, DMF, alcohol or their mixtures with other solvents with less solubilities by means of many times of classical recrystallization to reach effective resolution.
For economical and large scale synthesize the target chiral compounds and, in the same time, for solving problems of eliminate (storage) the “wastes” in the way of environmental protection, it is necessary to solve problems of racemization, recovery and utilization of the unwanted chiral compounds or intermediates, the recovery and recycle of the chiral resolving agents. WO 02/059128A2 etc. reported the racemization and recycle of the unwanted chiral (R)-Clopidogrel intermediate (VII), while they did not offer the details of racemization. US2004/0024012A1 disclosed the racemization of (R)-Clopidogrel with strong base (such as potassium t-butoxide), while the yield and ee value were not offered in the examples. US2005/0059696A1 reported a process of refluxing and racemization of unwanted chiral (R)-Clopidogrel in NaOH solution to obtain compounds (V) to realize the recovery and utilization.
In all the reported methods, several of following problems are still to be solved: (1) How to manufacture Clopidogrel and its methyl tetrahydrothienopyridine acetate analogues in an economical, effective, environmental protective, commercialize and industrialize way; (2) resolution efficiency; (3) the consumption amount and recycle or reuse of the chiral resolution agents such as camphor sulfonic acid and tartaric acid etc.; (4) selection and optimization of solvents and their consumption; (5) reliability and cost efficiency of resolution method used.